KR100486316B1 - New preparation method of 5,11-dihydro-6H-dibenz[b,e]azepin-6-one - Google Patents

Abstract

The present invention provides a 5,11-dihydro-6H-dibenz of the following structural formula (I) consisting of using a compound of the following structural formula (VI) as a reaction catalyst and using Friedel-Craft alkylation in an inert solvent. b, e] new process for preparing azepine-6-one.

5,11-dihydro-6H-dibenz [b, e] azin-6-ones prepared according to the present invention are useful intermediate compounds for the manufacture of pharmaceuticals, including antihistamines.

Description

New preparation method of 5,11-dihydro-6H-dibenz [b, e] azepin-6- one}

The present invention provides 5,11-dihydro-6H-dibenz [b, e] azin-6-one (or 5,6-dihydro-6) which is a compound of formula (I) -Oxomopantridine).

[Formula 1]

The compound of formula (I) is used for the synthesis of various pharmaceuticals, including the antihistamine 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride. It is useful as an intermediate. Accordingly, various studies on the preparation method of the compound of formula (I) have been conducted.

A general method for preparing the compound of formula (I) is Indian J. Chem. 23B, 165 (1984), German Patent No. 2431409, US Patent No. 3367930, German Patent No. 2505714, US Patent No. 3910890, and the like. Representative production methods of formula (I) described in these known production methods can be divided into three types as follows.

First, the method of preparing the compound of the target compound (I) by Beckman potential reaction of the compound of the formula (II) and

Scheme 1

Secondly, to prepare the desired compound (I) by reacting the compound of formula (III) with phosgene to produce formula (IV) and then using aluminum chloride as a catalyst;

Scheme 2

Third, a method for preparing the desired compound (I) by reacting the compound of formula (V) with hydrofluoric acid or aluminum chloride in a benzene solvent is known.

Scheme 3

However, the synthesis of the target compound (I) from the compound of the formula (II) using the Beckman potential reaction, which is the first of these methods, hardly occurs.

In addition, the second method of preparing the formula (IV) from the compound of the formula (III) is a very dangerous process because it requires the use of phosgene, a compound with strong toxicity. In addition, compound (III), which is used as a starting material, has to be prepared through a multi-step process.

Third, the method for preparing the compound of formula (I) from the compound of formula (V) should also be prepared using the toxic phosgene, which is also a starting material, and the solvent of benzene which is highly toxic in the reaction. It has a number of disadvantages, such as the use of hydrofluoric acid, and the use of hydrofluoric acid.

In the present invention, a method for preparing a target compound in high yield under mild and easy reaction conditions and solving various problems such as the use of a compound having a low yield and a toxic and corrosive compound, which are disadvantages of known methods in synthesizing the target compound, are provided. The purpose is to provide.

The present invention is characterized in that the desired compound (I) is prepared through intramolecular Friedel-Craft alkylation reaction using compound (VI) obtained through condensation reaction of o-chloromethylbenzoic acid chloride with aniline as a starting material.

The present invention will be described in more detail as follows.

The present invention provides a condensation reaction of o-chloromethylbenzoic acid chloride with aniline as shown in [Scheme 4] in preparing 5,11-dihydro-6H-dibenz [b, e] azin-6-one. The target compound (I) can be obtained through Friedel-Crafts alkylation using the compound of formula (VI) obtained as a starting material.

Here, o-chloromethylbenzoic acid chloride is a well-known compound widely used as an intermediate of agrochemicals and pharmaceuticals. Org. Chem. 40, 21, 3026 (1975) and WO 0142185 et al.

In the present reaction, aluminum chloride was used as a catalyst for the Friedel-Craft reaction, and an equivalent thereof was used in an amount of 1.0 to 10.0 equivalents based on the compound of formula (VI), and preferably around 2.0 equivalents. The reaction temperature is from room temperature to the reflux temperature of the solvent used, preferably from 90 ° C to 110 ° C. As the reaction solvent, solvents such as chlorine-containing hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride and nitrated alkanes such as nitrobenzene, nitroethane and nitromethane are used, and preferably nitromethane and nitrobenzene are used. The reaction time is about 1 hour to 24 hours, preferably about 5 hours to 6 hours.

Scheme 4

Hereinafter, the present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the invention thereto.

Reference Example 1

Synthesis of α-chloro-o-toluanilide

50 ml of toluene was dissolved in 6.27 ml (68.8 mmol) of aniline and 5.85 ml (72.3 mmol) of pyridine mixture, and the reaction mixture was cooled to 0 ° C. A solution obtained by dissolving 13.0 g (68.8 mmol) of o-chloromethylbenzoic acid chloride in 20 ml of toluene was added dropwise to the reaction solution while maintaining the temperature below 10 ° C, and reacted with stirring at room temperature for 1 hour. 20 ml of water was added to the reaction solution, and after further stirring at room temperature for 1 hour, the resulting crystalline compound was filtered to obtain a white target compound. On the other hand, the toluene layer of the filtrate was separated, washed with 1N aqueous hydrochloric acid solution and water, dried and concentrated to obtain the target compound. The desired compound obtained was obtained in a yield of 16.3 g (96% of theory).

Melting Point: 119.5 ~ 120 ℃

IR cm ^-1 (KBr): 3270, 3130, 3080, 1640, 1590, 1540, 1490, 1430, 1325, 1265

¹ H-NMR (CDCl ₃ ): δ (ppm) 4.84 (s, 2H), 7.15 (t, 1H, J = 7.5 Hz), 7.34-7.75 (m, 9H), 7.89 (br, 1H)

MASS m / z: 245 (M +)

Reference Example 2

After dissolving a mixture of 20 g (146 mmol) of phthalide, 0.27 g (4.4 mmol) of boric acid and 1.22 g (4.4 mmol) of triphenylphosphine oxide, 13.9 ml (190 mmol) of thionyl chloride was heated to about 130 ° C. It was added dropwise at the temperature of and stirred for 5 hours at the same temperature. 10 ml of toluene was added to the reaction mixture, followed by concentration. The concentrated solution was dissolved in 50 ml of toluene, and added dropwise to a mixed solution of 13.3 ml (146 mmol) of aniline, 13 ml (161 mmol) of pyridine, and 220 ml of toluene at a temperature of 10 ° C. or lower. The reaction was stirred at room temperature for 1 hour.

30 ml of water was added to the reaction solution, followed by further stirring at room temperature for 1 hour, and the resulting crystalline compound was filtered to give 27.6 g of a white desired compound (77% of theory).

Example 1

Synthesis of 5,11-dihydro-6H-dibenz [b, e] azin-6-one

After dissolving 8.36 g (62.7 mmol) of aluminum chloride in 70 ml of nitromethane, 7.0 g (28.5 mmol) of α-chloro-o-toluanilide was added and stirred under reflux for 6 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ice and hydrochloric acid, and stirred, and then the organic layer was separated. The separated organic layer was washed with water, dried and concentrated. The obtained material was recrystallized from 30 ml of toluene to yield 5,11-dihydro-6H-dibenz [b, e] azepine- in 4.3 g yield (71% of theory). 6-one was obtained.

Melting Point: 200 ~ 201 ℃

IR cm ^-1 (KBr): 3190, 3030, 2980, 2910, 1650, 1590, 1570, 1490, 1450, 1440, 1380

¹ H-NMR (CDCl ₃ ): δ 3.87 (s, 2H), 7.00 ~ 7.27 (m, 6H), 7.37 (t, 1H, J = 7.5Hz), 7.86 (d, 1H, J = 7.7Hz)

MASS m / z: 209 (M +)

Example 2

After dissolving 2.18 g (16.3 mmol) of aluminum chloride in 5 ml of nitrobenzene, 2.0 g (8.1 mmol) of α-chloro-o-toluanilide was added and stirred under reflux overnight. After cooling to room temperature, the reaction mixture was poured into a mixture of ice and hydrochloric acid, and stirred, and then the organic layer was separated. The separated organic layer was washed with water, dried and concentrated, and the obtained material was separated by column chromatography, yielding 0.6 g (45% of theory) of 5,11-dihydro-6H-dibenz [b, e] azepine- 6-one was obtained.

The production method according to the present invention provides a method for producing the target compound and the similar compound in high yield by using aluminum chloride having low toxicity and corrosion resistance as a catalyst and carrying out the reaction under mild reaction conditions.

Claims (3)

Next, a method of preparing 5,11-dihydro-6H-dibenz [b, e] azin-6-one represented by Formula 1 through an intramolecular Friedel-Craft alkylation reaction of the compound represented by Formula 2; [Formula 1] [Formula 2] The method of claim 1, wherein aluminum chloride is used as the reaction catalyst. The process according to claim 1, wherein a solvent selected from nitromethane, nitroethane, nitrobenzene, chloroform, methylene chloride, carbon tetrachloride and 1,2-dichlorobenzene is used as the reaction solvent.